Characterization of a novel membrane protein potentially involved in TGF-Beta signaling In both flies and vertebrates, members of the TGF-B family of growth factors play prominent roles in embryonic pattern formation and in the regulation of cell growth and proliferation. In humans, there are many strong links between mutations in various components of TGF-Beta signaling pathways and tumor formation. In recent years, a lot of progress has been made toward understanding the mechanism of TGF-B signaling and cell cycle arrest. However, the mechanisms, how Activins and TGF-Betas can promote and inhibit cell proliferation in different tissues, are not known. Drosophila contains substantially fewer genes than vertebrate genomes. It only encodes seven TGF-Beta-type ligands signaling through three type I receptor and two SMAD transcription factors. We find that two of the ligands, dActivin and Anti-Activin, signal through the same type 1/11receptors and activate both dSMAD1 (MAD), which is primarily activated by DPP, and dSMAD2. However, the two ligands exhibit opposite effects in vivo. When overexpressed in wings, dActivin signaling through dSMAD1 promotes growth, while Anti-Activin also signaling through dSMAD1 inhibits growth. This result indicates that the TGF-Beta signaling pathway may be more complex than the characterized type VII receptor/SMAD pathway. In this proposal, we describe a new type of membrane protein that may function in TGF-Beta signaling. In a genetic screen, we have isolated a mutation that strongly interacts with DPP signaling similarly to dSMAD1 and Medea. Our analysis suggests that the mutated gene most likely encodes an evolutionary highly conserved gene that encodes a transmembrane protein with multiple isoforms. We have obtained at least four alleles of this gene from EMS mutagenesis screens and an additional allele by P-element mobilization. The strongest allele is embryonic lethal, and homozygous clones are cell-lethal. The goal of this proposal is to prove that these phenotypes are caused by mutations in this novel transmembrane protein and to characterize the molecular nature of individual mutant alleles. This project has great potential to contribute new insights into the mechanism of TGF-Beta signaling and our understanding of the development of certain cancers. It may also provide a new target to combat these diseases.